This proposal builds upon the already established collaborative relationship between Oncogen, Inc., a subsidiary of Bristol-Myers Corporation and the University of Washington Primate Center and Departments of Medicine to develop and test candidate HIV vaccines. Project 1 involves the development and construction of candidate HIV1, HIV2 and SIV subunit vaccines. Vaccinnia recombinants that express on infected cells the envelope and gag proteins of HIV1 (LAV1 strain), HIV2 (LAV2) strains) and SIV (MNIV strain) will be constructed. Similar recombinant vaccines will be cloned into a baculovirus vector and these subunit proteins purified and mixed with an adjuvant. In Project 2, the immunogenicity, tolerance, and protection rate of these constructs will then be tested in the macaque nemistrina primate model. Detailed evaluations of the host response after vaccination will be performed including antibody responses to HIV/SIV polypeptides, neutralizing antibodies to homologous and heterologous strains of virus and ADCC activity. Cellular immune responses including lymphoproliferative responses to mitogens, soluble antigens, and HIV and vaccinia antigens will be assayed as will evaluation of T cell cytotoxicity to HIV utilizing EBV transfected B cells expressing HIV and/or SIV antigens (Project III). Antibody response after vaccination to synthetic peptides to envelope and core regions of SIV and HIV-2 will also be determined (Project IV). Challenge studies to evaluate the efficacy of each of these candidate vaccines in preventing infection, viremia and subsequent immunodeficiency disease will be performed. HIV-l and HIV-2 subunit vaccines that are well tolerated and immunogenic in primates will then be tested in humans (Project 5). Comparison of the humoral and cellular immune responses between these 2 subunit vaccine approaches, between various genomic constructs and between primates and humans will provide critical information about the protective immune responses to HIV infection and define subunit HIV vaccines which are worthy of future clinical trials.